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Mechanism of CX3CR1+ macrophage-mediated resolution of eosinophilic allergic lung inflammation

Award Number: R01HL153170
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/10/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Mechanism of CX3CR1+ macrophage-mediated resolution of eosinophilic allergic lung inflammation - Title: Mechanism of CX3CR1+ macrophage-mediated resolution of eosinophilic allergic lung inflammation Abstract: Recent studies show that tissue-resident macrophages participate in not only the initiation of inflammation but also in the resolution and prevention of local inflammation. To precisely determine the subsets of macrophages engaged in resolving lung inflammation and gain insight into their functions, we adopted new techniques of mass cytometry and single-cell RNA-seq (sc-RNA-seq) to analyze human and mouse macrophages in the lung. Our supporting data showed that alveolar macrophages (AMs) are phenotypically diverse and highly dynamic in response to allergen challenge. Based on the sc-RNA-seq data, AMs can be clustered into a few groups at a steady status. Among these groups, a subset of CX3CR1-expressing AMs (CX3CR1+ AMs) are unique in terms of their phenotype and patterns of gene expression, compared to classical resident AMs which are CX3CR1 negative. In patients with allergic asthma and a mouse model of asthma, we found that CX3CR1+ AMs are markedly increased in BAL by allergen challenge. The CX3CR1+ AMs express not only the macrophage but also eosinophil markers such as human Siglec-8. Further investigation with the CX3CR1- reporter and Epx-cre (a.k.a. Eo-cre) reporter mice reveals that CX3CR1+ macrophages engulf eosinophils at a steady state and in allergic lung inflammation. Depletion of CX3CR1+ macrophages in mouse models resulted in spontaneous tissue eosinophilia at a steady status and prolonged tissue eosinophilia in allergic lung inflammation. Based on this data, we hypothesized that the newly recruited CX3CR1+ AM subset promote the clearance of tissue eosinophils and facilitates the resolution of allergic lung inflammation. In aim 1, we will focus on the cellular dynamics of CX3CR1+ macrophages in allergic lung inflammation. Regarding the molecular mechanism of CX3CR1+ mediated-eosinophil clearance, we examined the potential ligands for CX3CR1 – CX3CL1 and CCL26. We discovered that CCL26 plays a key role in activating CX3CR1+ macrophages, whereas CX3CL1 is indispensable. Our sc-RNA-seq data revealed that CX3CR1+ AM subset is the sole source of the transcript of C1q - a key molecule for efferocytosis. In in-vitro setting, CCL26 triggers CX3CR1+ macrophages to secrete C1q in a CX3CR1 receptor-mediated manner. Furthermore, C1q and CCL26 are increased in BAL by allergen challenge in patients with allergic asthma. This data suggests CCL26 activates CX3CR1+ macrophages to facilitate efferocytosis via C1q secretion. In aim 2, we will examine the detailed mechanisms of CX3CR1+ macrophage activation through CCL26-mediated C1q secretion. Finally, we will extend the study to translational human research using the IRB-approved protocol for the segmental provocation with an allergen to evaluate the human relevance of the above proposed experiments. The proposed study is based on our strong supporting data on the new roles of CX3CR1+ macrophages in the resolution of allergic lung inflammation. This study will lead to a better understanding of the resolution process of allergic asthma.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	5	12/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $565,617 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	001	5	7/24/2025	NON-COMPETING CONTINUATION	$56,561
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	5	3/25/2025	NON-COMPETING CONTINUATION	$509,056
														Subtotal = $565,617

Issue Date FY: 2024 ( Subtotal = $554,305 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	001	4	6/24/2024	NON-COMPETING CONTINUATION	$45,249
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	4	2/7/2024	NON-COMPETING CONTINUATION	$509,056
														Subtotal = $554,305

Issue Date FY: 2023 ( Subtotal = $565,617 )
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	3	2/17/2023	NON-COMPETING CONTINUATION	$565,617
														Subtotal = $565,617

Issue Date FY: 2022 ( Subtotal = $585,605 )
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	2	5/20/2022	NON-COMPETING CONTINUATION	$585,605
														Subtotal = $585,605

Issue Date FY: 2021 ( Subtotal = $585,605 )
2021	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	1	5/10/2021	NEW	$527,045
2021	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	001	1	6/23/2021	NEW	$58,560
														Subtotal = $585,605

Grand Total All Awards = $2,856,749

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Mechanism of CX3CR1+ macrophage-mediated resolution of eosinophilic allergic lung inflammation

Award Number: R01HL153170

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/10/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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